Note: Descriptions are shown in the official language in which they were submitted.
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TRANSDERMAL DRUG DELIVERY SYSTEM
Background of the Invention
The present invention relates to a transdermal delivery system for local
anesthetic, immunosuppresive aid neurologically effective drugs, as well as
for
polypeptides and protein-based drugs. More particularly, the present invention
relates
to a transdermal delivery system for such drugs as granisetron, (idocaine, and
cyclosporine in a transdermal drug delivery system (TDDS).
The present invention is a modification of the invention described and claimed
in WO 02109763.
In WO 02/09763 there is described and claimed a transdermal delivery system
for analgesic, anti-pyretic and anti-inflammatory drugs comprising an
analgesic, anti-
pyretic or anti-inflammatory drug in combination with water-miscible
tetraglycol and
water for dissolving said drug in hydrogel form.
As stated, WO 02!09763 teaches a transdermal. delivery system especially
useful for non-steroidal-anti-inflammatory drugs.
It has now been found that not only non-steroidal-anti-inflammatory drugs can
be effectively transported across the skin by the drug delivery system
described in said
Specification, but that many other types of active molecules may also be
delivered
transdermally utilizing a combination of water-miscible tetraglycol and water
for
dissolving such drugs in hydrogel form and this especially when said
transdermal
delivery system, is in the form of a microemulsion. Thus it has now been
discovered
that by mixing a drug model and tetraglycol in a microemulsion, in a plain
solution as
well as in patches or hydrogels containing an . ionized polymer, the obtained
drug
delivery system resulted in an enhanced percutaneous permeation thus increased
the
drug's potential of curing, healing or improving its therapeutic effect.
Thus according to the present invention there is now provided a transdermal
delivery system for local anesthetic, immunosuppresive and neurologically
effective
drugs, as well as for polypeptides and protein-based drugs. comprising a local
anesthetic, immunosuppresive or neurologically effective . drug, as well as a
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2
polypeptide or protein-based drug in combination with water-miscible
tetraglycol
and water for dissolving said drug in hydrogel form.
In preferred embodiments of the present invention said drug is selected from
the
group consisting of granisetron, lodocaine, and cyclosporine.
The novel transdermal drug delivery system (TDDS) is preferably applied using
a unilayer polymeric patch with adhesive margins, providing an effective and
convenient mode of drug delivery.
In principle, transdermal administration of medications has several.
advantages:
elimination of variations in plasma concentration after gastrointestinal
absorption,
elimination of hepatic first pass metabolism, and avoidance of
gastrointestinal
intolerance. The dermal administration of drugs may produce less
gastrointestinal, (GI)
adverse reactions as compared with the oral route, as it is assumed that some
of the
GI adverse effects are due to the local action of the drug (e.g., in stomach).
The
transdermal route of administration may be of particular significance in
infants and in
children because of their greater surface area to weight ratio. The epidermis
of the full
term neonate (but not that of the premature infant) is well developed and
similar to that
of an older child or adult. But the thinner skin with relatively rich blood
supply of the
infant and child, may affect the pharmacokinetics of drugs administered by
transdermal
delivery systems, this has obvious therapeutic advantages, but it may have
also toxic
significance (the majority of cases of percutaneous drug toxicity have
occurred in
infants: aniline dye, hexachlorophene, iodine, and alcohol poisoning).
Transdermal
drug absorption can significantly alter drug kinetics depending on a number of
factors,
such as site of application, thickness and integrity of the stratum corneum
epidermis,
size of the molecule, permeability of the membrane of the transdermal drug
delivery
system, state of skin hydration, pH of the drug, drug metabolism by skin
flora, lipid
solubility, depot of drug in skin, alterations of blood flow in the skin by
additives and
body temperature.
While topical drug delivery systems have been used for centuries for the
treatment of local skin disorders, the use of the skin as a route for systemic
drug
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3
delivery is of relatively recent origin. Transdermal administration of drugs
has been
established in adults in relation to nitroglycerine, estrogens, scopolamine,
and
fentanyl. Although lacking adequate pediatric studies, scopolamine and
fentanyl are
often used in pediatric patients by this route. There are data on the
pharmacokinetics
and clinical use of transdermal administration of theophylline in human
neonates: after
a .single application to the skin an hydrogel disc system resulted in
therapeutic
concentrations of theophylline for. up to 3 days in neonates with apnea.
Many drugs are practically insoluble in water or slightly soluble even in
their
ionized form. Therefore, dissolution of active agents in topical and
transdermal
preparations usually requires incorporation, of an alcohol. However, the use
of solvents
like alcohols in topical preparations may lead to precipitation of the drug on
the skin
upon evaporation of the solvent once spread over the skin area. In situations
in which
the application.area is occluded, such as in transdermal patches, alcohol
presence
may cause a skin irritation and inflammatory'conditions,
The present invention obviates this problem since it enables the preparation
of
transdermal delivery systems for drugs usually requiring alcohol for the
dissolution
thereof, utilizing water-miscible ~etraglycol instead of the standard alcohols
used
heretofor.
Thus, the present invention also provides a transdermal delivery system for an
alcohol-miscible drug comprising an alcohol-miscible local anesthetic,
immunosuppresive or neurologically effective drug, as well as a polypeptide or
protein-
based drug in combination with water-miscible tetraglycol and water for
dissolving said
drug in hydrogel form wherein said transdermal delivery system is in the form
of a
microemulsion. '
Another aspect of the present invention comprises the method of preparing
transdermal drug delivery systems. This method includes preparation of 'easy-
to-make'
patches containing the drug, tetraglycol and other ingredients, which adhere
spontaneously to the skin surface. The manufacturing method of transdermal
patches
of the present invention is unique by the virtue of the guar-based polymer to
solidify
the drug-containing liquid~within few minutes to a patch at any desired size,
shape and
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4
thickness. The manufacturing of the composition can be designed in such a way
that
once the polymer is dispersed in a liquid mixture containing the drug in a
tetraglycol-
containing microemulsion, the mixture is molded to a patch - a process that
takes few
minutes at the best case to several hours at the worst. The. obtained patch is
self-
adhesive to the skin surface, requiring only a covering sheet with adhesive
margins to
occlude the system from any kind of evaporation or contamination during
treatment.
Detailed Description of the Invention
It should be defined, that by the term "comprising" as used in the present
invention is meant that various other inactive ingredients, compatible drugs
and
medicaments can be employed in the compositions, as long as the critical
tetraglycol.or
ionized polymers are present in the compositions and are used in the manner
disclosed.
All percentages herein are by weight unless otherwise specified.
As stated hereinbefore, the transdermal delivery systems of the present
invention comprise an effective amount of:
(a) a local anesthetic, immunosuppresive or neurologically effective drug, as
well as a polypeptide or protein-based drug, or combinations of such drugs;
and
(b) the water-miscible tetraglycol (TG), which can be mixed with any portion
of
water. ,
In addition, the transdermal systems of the present invention preferably
include
further components as follows:
(c) in the case where the composition according to the invention is a gel,
soft or
hard patch, stabilizers or shape-forming agents are selected from the group
consisting
of ionized polymers such as cationized guar gum, cellulose derivatives,
acrylic
polymers, polysaccharides, lipids, proteins, and polyhydroxy compounds. The
average
molecular weight of these polymers can vary from 5,000 to 500,000 daltons. The
preferred polymer for the transdermal patch of the present invention is
hydroxypropyl .
guar~hydroxypropyltrimonium chloride (guar-based polymer, GP);
(d) in case that the composition is an emulsion, the oil phase comprises at
least
one ester selected from the group consisting of monoglycerides, diglycerides
and
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triglycerides of monocarboxylic acids selected from the group consisting of
saturated
monocarboxylic acids and monocarboxylic acids containing ethylenic
unsaturation.
The emulsion is prepared by using pharmaceutically acceptable emulsifiers
containing
at least one esterified carboxylic group in its structure.
Further preferred components include:
(e) poly- or oligo- hyroxy compounds or their derivatives as co-solvents.
These
compounds can be selected from the group of polyalkylene glycols, poloxamers,
and
di- or tri- ethylene glycol ethyl ethers;
(f) skin penetration enhancers selected from nonionic surfactants consisting
of
'sorbitan sesquioleate, cetostearyl alcohol, polysorbate 60, sorbitan
monostearate,
sorbitan monooleate, and a preferred combination of polyoxyethylene 23 lauryl
alcohol
and glyceryl monoldi-oleate;
(g) safe and effective preservatives such as parabens, benzyl alcohol and
benzoic acid. pH adjusting agents such as triethanolamine, citric and lactic
acid may
also be included in the composition.
Preferred compositions according to the present invention are pharmaceutically
accepted and easy-to-apply skin-adhesive systems containing NSAIDs as active
ingredients. More particularly, these systems composed of tetraglycol
(glycofurol,
tetrahydrofurfuryl alcohol polyethyleneglycol ether) (TG) and an ionized
polymer such
as hydroxypropyl guar hydroxypropyltrimonium chloride (guar-based polymer,
GP),
which assist in dissolving or solubilizing the active materials in a hydrogel
form, and
facilitate their penetration through the lipophilic strata of the skin.
While the invention will now be described in connection with certain preferred
embodiments in the following examples and with reference to the accompanying
figures so that aspects thereof may be more fully understood and appreciated,
it is not
intended to limit the invention to these particular embodiments. On the
contrary, it is
intended to cover all alternatives, modifications and equivalents as may be
included
within the scope of the invention as defined by the appended claims. Thus, the
following examples which include preferred embodiments will serve to
illustrate the
practice of this invention, it being understood that the particulars shown are
by way of
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6
example and for purposes of illustrative discussion of preferred embodiments
of the
present invention only and are presented in the cause of providing what is
believed to
be the .most useful and readily understood description of formulation
procedures as
well as of the principles and conceptual aspects of the invention.
In the drawings:
Fig. 1 is a graphical representation of the percutaneous penetration of
graniset.ron.
Fig. 2, 3, 4a, 4b and 5 are graphical representations of the percutaneous
penetration of lidocaine.
Fig. 6a and 6b are graphical representations of the concentrations of
cyclosporine found in the epidermal (A) and dermal (B) layers and
Fig. 7 is a. graphical representation showing the partitioning of cyclosporine
between the dermis and epidermis.
Example I - Granisetron
This example is a study performed in vitro using porcine ear skin as described
below:
Diffusion cells: The permeability of granisetron through porcine skin was
measured in-vitro with a Franz diffusion cell system. The diffusion area was
1.767 cm2
(15 mm diameter orifice), and the receptor compartment volumes varied between
11 to
12 ml. The solutions on the receiver side were stirred by externally driven,
teflon-
coated magnetic bars.
Skin preparation: Full-thickness porcine skin was excised from fresh ears of
slaughtered white pigs (breeding of Landres and Large White, locally grown in
Kibbutz
Lahav, Israel). Skin sections (about 2X2 cm) were 'cut and subcutaneous fat
was
removed from the skin sections with a scalpel. Transepidermal water loss
measurements (TEWL, Dermalab~ Cortex Technology, Hadsund, Denemark) was
performed and only those pieces that the TEWL levels were within specification
(<10
glmZh) were mounted in the diffusion cells.
Permeation study: 200 mg specimens of three granisetron preparations [5%
aqueous solution, 5% in tetraglycol-containing microemulsion, and 5%
granisetron in a
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same microemulsion gelled with ionized polymer - see Table 1 below] were
applied on
the skin. The receiver solutions (PBS, pH 7.4) were sampled at predetermined
time
intervals, and the cells were.replenished to their marked volumes with fresh
buffer
solution. Samples were kept at -20oC until analyzed by HPLC. .
Calculations: As a result of a large volume sampling from the, receiver
solution
and replacing with equal volumes, the solution is constantly diluted. Taking
this into
account, cumulative drug permeation (Qt) is calculated from the following
equation:
t-1
Qt = UrCt +~ VSC,
i=0
where Ct is the drug concentration of the receiver solution at each sampling
time, C; is
the drug concentration of the i-th sample, and V~ and VS are volumes of the
receiver
solution and the sample, respectively. Data were expressed as the cumulative
granisetron permeation per unit of skin surface area, Qt/S (S=1.767cm2).
Results: Figure 1 shows the differences found between the 3 formulations
tested. The percutaneous penetration of granisetron increased significantly
when a
tetraglycol-containing microemulsion was applied on the skin (3.84 ~,g/cm2lhr
vs. 0.60
~g/cmZ/hr), however, it increased even more (up to 10.06 ~,glcm2/hr) when the
guar-
based ionized polymer was incorporated.
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Table 'I - Granisetron
Formulations
Ingredients 5% GRN in 5% GRN in 5% GRN in
an aqueous
microemulsionmicroemulsionsolution
gel liquid
n ~ i i
Granisetron 0.125 g 0.125 g 0.05 g
Distilled water 0.5 ml 0.5 ml 0.95 ml
.
Tetraglycol (TG)0.375 g 0.875 g -------
ISOprOpyl palrrlltate0.25 g 0.25 g ----
Arlacel 186 0.25 g 0.25 g -------
Chremophor RH40 0.50 g 0.50 g . -------
Jaguar C-162 0.50 g ------- ----
~ VKN = granisetron
~ Chremophor RH40 = polyoxyl 40 hydrogenated castor oil USP24/NF19 (PEG-40
hydrogenated
castor oil) [Manufacturer: BASF, Germany].
~ Arlacel 186 = glyceryl oleate [Manufacturer: Uniqema, UK].
~ Jaguar C-162 - guar-based polymer (Guar gum, 2-hydroxypropyl 2-hydroxy-3-
(trimethylammonio)propyl . ether chloride; CTFA/INCI name: . Hydroxypropyl
guar
hydroxypropyltrimonium chloride) (Manufacturer: Rhone-Poulenc, France]. .
Example II - Lidocaine
This example includes experiments that were performed in vitro using excised
rat skin and in vivo in rats as described below:
In vitro: The diffusion testing, skin preparation, permeation and calculations
were pertormed exactly as descr;bed for granisetron, except that the skin was
taken
from the abdominal side of Sprague-Dawley rats. The rats (around 500 g) were
killed
by aspiration of ethyl ether vapors and the abdominal hair was then trimmed
off with a
hair clipper. Sections of full-thickness abdominal skin were excised from the
fresh
carcasses of the animals. Subcutaneous fat was removed with a scalpel, and the
skin
sections were mounted in the diffusion cells. The skin was placed with the
stratum
corneum facing up on the receiver chambers, and then the donor chambers were
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clamped in place. The excess skin was trimmed off and the receiver chamber,
defined
as the side facing the dermis, was filled with phosphate buffer (4mM, pH=7.4).
In vivo: The in-vivo skin penetration was evaluated in anesthetized rats.
Anesthetized (15 mglkg pentobarbital sodium i.p.) rats (Sprague-Dawley, 250-
300g)
were placed on their back, the abdominal hair was trimmed off, and the skin
was
washed gently with distilled water. Drug-containing preparations were applied
on a
restricted skin surface (4.9 cm2).. Blood samples were taken from the tail
vein into
heparanized tubes at t=0, 1, 2, 3, 4, 5, and 6 hours from the time of drug
application. In
a separated study 18 anesthetized rats were applied with (a) 2.5% lidocaine
base in
tetraglycol-containing microemulsion gelled with guar-based ionized polymer
[n=9],
and (b) a commercial product known as EMLA 5% cream (Astray containing 2.5%
lidocaine (as base) and 2.5% prilocaine [n=9]. After 15, 30 and 60 minutes of
in vivo
study (3 animals were designated for each time and for each group), the
products were
removed from the animals and they were killed by aspiration of ethyl ether.
The drug-
exposed skin areas were swabbed 3-4 times with 3 layers of gauze pads, washed
for
30 seconds with running water, wiped carefully and harvested from the animals.
The
excised skin sections were rinsed with phosphate buffer (pH=7.4), and heat-
separated
(60°C, 60 seconds) to its epidermal and dermal layers. Each layer was
cut to small
pieces and inserted in 2-ml .vials. The tissue in each vial was extracted by
ethyl
alcohol. Each extraction was performed by incubation in a 40°C shaking
water bath
(150 rpm) for 1 hour. The extracts were injected into the HPLC system.
Formulations tested in-vitro and in-vivo (see Table 2):
(a) 2.5% lidocaine (as base) in tetraglycol-containing microemulsion liquids
(b) 2.5% lidocaine (as base) in tetraglycol-containing microemulsion gels
prepared
with guar-based ionized polymer.
(c) Commercial product as reference: EMLA 5% cream (Astray containing 2.5%
lidocaine (as base) and 2.5% prilocaine.
Results: Figure 2 presents the profiles of percutaneous penetration kinetics
of
lidocaine hydrochloride delivered from tetraglycol-containing microemulsions.
It can be
seen that by combining the ionized polymer, the penetration through the skin
was
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accelerated significantly. This increase in the drug penetration may be
explained by
neutralization of lidocaine HCI to lidocaine base by the polymer, thus raising
drug
lipophilicity. The relatively higher penetration of lidocaine base from a
microemulsion
liquid, which is also demonstrated in the Figure, supports this hypothesis.
Nevertheless, as observed in Figures 3 and 4, there has been found some
difference
between the penetrations of hydrochloride and the base molecules in gels. A
higher
penetration of the base was repeatedly noted only during the first hours of
gel
application, implying that the base is superior over the hydrochloride in
advancing the
onset time of the local anesthetic effect. It has also been found (Figure 4)
that more
lidocaine base penetrated from the gel than from the patented commercial EMLA
cream (also containing lidocaine basse).
While the in vitro penetration showed quantitative amounts of penetrating
drug, the
in vivo study failed to show systemic plasma levels that were above the limit
of HPLC
assay quantitation. To extrapolate the penetration rates of drug quantities
across the
skin (fuxes), it was necessary; therefore,v to monitor the drug in the skin
layers. Figure
5 presents the partitioning of lido~aine between the dermis and the epidermis
after an
in vivo study. The figure clearly shows that within an hour, a relatively
higher portion of
the cutaneous drug accumulated in the dermis of skin treated with the
tetraglycol gel.
In contrast, EMLA cream delivered more drug to, the epidermis with a lower
drug
partitioning in the dermis, indicating a slower penetration of lidocaine
across the full-
thickness skin that results in lower drug levels in the subcutis and the
surrounding
tissues.
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Table 2 - Lidocaine
Formulations
2.5% LID-base2.5% LID-HCI 2.5~0 lidocaine
in (HCI or
Ingredients in microemulsion base) in microemulsion
,
liquid
microemulsiongel
gel
Lidocaine 0.125 g as 0.125 g as 0125 g as base
base base
Distilled water1 ml 1 ml 1 ml
Tetraglycol 0.875 g 0.875 g 1.875 g
(TG)
Isopropyl 0.5 g 0.5 g 0.5 g
pal mitate
Arlacel 186 0.5 g 0.5 g 0.5 g
Chremophor 1 ~0 9 1.0 g 1.0 g
RH40
Jaguar C-162 1.0 g 1.0 g
~ LID = Lidocaine
~ Chremophor RH40 = polyoxyl 40 hydrogenated castor oil USP24/NF19 (PEG-40
hydrogenated
castor oil) [Manufacturer: BASF, Germany].
~ Arlacel 186 = glyceryl oleate [Manufacturer: Uniqema, UK].
~ Jaguar C-162 - guar-based polymer (Guar gum, 2-hydroxypropyl 2-hydroxy-3-
(trimethylammonio)propyl ether chloride; CTFA/INCI name: Hydroxypropyl guar
hydroxypropyltrimonium chloride) [Manufacturer: Rhone-Poulenc, France].
Example III - Cyclosporine
This example includes experiments that were performed in vivo in rats as
described below:
The in-vivo skin penetration was evaluated in anesthetized rats. Anesthetized
(15 mg/kg pentobarbital sodium i.p.) rats (Sprague-Dawley, 250-300g) were
placed on
their back, the abdominal hair was trimmed off, and the skin was washed gently
with
distilled water. Drug-containing preparations were applied on a restricted
skin surface
(4.9 cm~). After 2 and 4 hours of in vivb study (3 animals were designated for
each time
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and for each group), the products were removed from the animals and they were
killed
by aspiration of ethyl ether. The drug-exposed skin areas were swabbed 3-4
times with
3 layers of gauze pads, washed for 30 seconds with running water, wiped
carefully and
harvested from the animals. The excised skin sections were rinsed with
phosphate
buffer (pH=7.4), and heat-separated (60°C, 60 seconds) to its epidermal
and dermal
layers. Each layer was cut to small pieces and inserted in 2-ml vials. The
tissue in
each vial was extracted by ethyl alcohol. Each extraction was performed by
incubation
in a 40°C shaking water bath (150 rprn) for 1 hour. The extracts were
injected into the
HPLC system. ,
Test formulations (see Table 3):
(a) 0.5% cyclosporine in propylene glycollpolyethylene glycol (PEG) 400
(b) 0.5% cyclosporine in tetraglycol-containing gel prepared with guar-based
ionized polymer.
Results: Figure 6 presents the concentrations of cyclosporine found in the
epidermal (A) an'd dermal (B) layers. After application of 0.5% drug solution
containing
propylene glucol as a commonly used enhancer, it was obvious that cyclosporine
massively accumulated in the epidermis while no drug was detected in the
dermis. In
contrast, a gel containing,0.5% cyclosporine in tetraglycol delivered the drug
into the
dermis at levels of upto 100 ng/cm2 skin surface area after 4 hours. No
difference was
noted between gels containing 20% and 10% ionized polymer (Table 3). Figure 7
illustrates the results differently by showing the partitioning of
cyclosporine between
the dermis and the epidermis. The figure clearly shows that already after 2
hours, a
relatively high portion (about 4%) of the cutaneous drug accumulated in the
dermis of
skin treated with the tetraglycol-ionized polymer. The portion of drug entered
into the
dermis was increasingly growing during the~next 2 hours. No drug fraction was
found in
the dermis after a topical solution of PEG-propylene glycol was used.
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Table 3 - Cyclosporine
Formulations
TG gel ~ TG gel PEG solution
Ingredients 20% polymer 1p% polymer
Cyclosporine 50 mg 50 mg 50 mg
.
Propylene glycol , 1.0 g
PEG 400 ' g,g5 g
. Distilled 3 ml 3 ml
water
Tetraglycol 4.95 g 5.95 g
(TG~
Jaguar C-162 2.0 g 1.0 g
PEG 400 = polyethylene glycol 400 (or polyoxyethylene glycol 400, Macrogol
400)
~ Jaguar C-162 - guar-based polymer ~ (Guar gum, 2-hydroxypropyl 2-hydroxy-3-
(trimethylammonio)propyl ether chloride; CTFAIINCI name: Hydroxypropyl guar
hydroxypropyltrimonium chloride) [Manufacturer: Rhone-Poulenc, France].
It will be evident to those skilled in the art that the invention is 'not
limited to the
details of the foregoing illustrative examples and that the present invention
may be
embodied in other specific forms without departing from the essential
attributes
thereof, and it is therefore desired that the present embodiments and examples
be
considered in all respects as illustrative and not restrictive, reference
being made to
the appended claims, rather than to the foregoing description, and all changes
which
come within the meaning and range of equivalency of the claims are therefore
intended to be embraced therein.
